tbuckley/cabot-search huggingface dataset:
Retrospective analysis of drug intake affecting the intestinal microbiota and the therapeutic effects of chemotherapy on gastric cancer.
Authors: Takeaki Nakamura, Ryosuke Watanabe, Takahiro Yamamura, Kazuaki Harada, Yasuyuki Kawamoto, Satoshi Yuki, Naoya Sakamoto, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2023)

379 Background: Administration of some medications, such as antibiotics, antacids, and probiotic supplementation, may affects the treatment outcomes of immune checkpoint inhibitors (ICIs), through the change of gut microbiota in cancer patients. Even when ICIs are combined with cytotoxic chemotherapy (Chemo), a use of such medications is expected to be a potential biomarker. However, the impacts of medications that affect gut microbiota on the efficacy of Chemo alone is unclear. Methods: We retrospectively analyzed patients who received fluoropyrimidines and platinum-based therapy for advanced gastric cancer in our institutions between January 2010 and December 2019. Progression-free survival (PFS) and overall survival (OS) by history of antibiotic/antacid/probiotic supplementation, were analysed. Results: A total of 101 pts were analyzed. Median age was 66 years (range, 30-81), female/male; 36/65, 1st-line regimen SP/XP/SOX/XELOX/FOLFOX; 52/2/39/1/7. In all patients, The median PFS for first-line treatment was 5.8 months (95% CI: 5.0-7.3) and the median OS was 15.5 months (95% CI: 12.5-18.6).Univariate analysis for PFS of first-line treatment did not show a significant difference in antibiotic use (median 7.6 vs 5.5 months, HR: 0.79 [95%CI: 0.50-1.24], p=0.31), oral antacids (median 6.6 vs 5.8 months, HR: 0.96 [95%CI: 0.61-1.54], p=0.89) and probiotic supplementation (median 9.1 vs 5.5 months, HR: 0.7 [95%CI: 0.38-1.26], p=0.24). Similarly in OS, the use of antibiotics (median 18.4 versus 13.4 months, HR: 0.85 [95%CI: 0.53-1.37], p=0.49), oral antacids (median 16.3 vs 13.8 months, HR: 1.15 [95%CI: 0.70-1.88], p=0.58), and oral probiotic supplementation (median 20.2 vs 13.8 months, HR: 0.77 [95%CI: 0.42-1.40], p=0.40), with no statistically significant differences. Conclusions: In this study, there were no significant differences in PFS and OS between patients administered with or without antibiotics, antacids, or probiotic supplementation. Future studies are expected to investigate the impacts of these medications on the treatment outcomes of ICIs+Chemo combination.
An indirect assessment of individual-level association between disease-free survival (DFS) and overall survival (OS) for resectable esophageal or gastroesophageal junction cancer (EC/GEJC): A pooled analysis of randomized controlled trials (RCTs) by an illness-death model.
Authors: Oguzhan Alagoz, Jaffer A. Ajani, Swetha Srinivasan, Inkyu Kim, Prianka Singh, Murat Kurt
Journal: Journal of Clinical Oncology (2023)

369 Background: Validation of intermediate endpoints such as DFS as surrogates for overall survival (OS) in RCTs at individual-level remains as a challenge due to difficulty of collection of individual-level patient data. This study explores the individual-level correlation between DFS and OS indirectly using reconstructed Kaplan-Meier (KM) curves from the RCTs assessing therapies for (neo)adjuvant and perioperative treatment of EC/GEJC. Methods: An illness-death model previously validated in estimating individual-level association between DFS and OS for four correlation meta-analyses, two of which were published by the GASTRIC group, in early and late stage treatment of gastric cancer was employed. Reconstructed DFS and OS data from 25 RCTs published between 1994 - 2020 was pooled separately for each arm and each endpoint. Pooled data was analyzed to estimate the correlation between DFS and OS, as measured by Pearson’s r, Spearman’s rho, and Kendall’s tau. Predictive accuracy of the approach was evaluated by comparing its OS and restricted mean survival time (RMST) predictions to their counterparts obtained from the reported OS data from the RCTs. Sensitivity of correlation measures were assessed with respect to pre-specified variations in pre-recurrence death probability, post-recurrence mortality rate, and choice of the survival model used to extrapolate reported DFS curves from the RCTs. Results: Across all RCTs, the primary cancers covered were EC (n=13), EC/GEJC(n=9), GEJC (n=2) and GEJC/gastric cancer (n=1). According to the histology, 10 RCTs studied only squamous cell carcinoma (SCC) and 9 RCTs studied only adenocarcinoma (AC) of the disease, whereas the remaining 6 RCTs included varying mixtures of SCC and AC patients. The follow-up duration ranged between 27 and 72 months across RCTs. Comparator and intervention arms of the pooled data had 2499 and 2490 patients, respectively. Predicted Pearson’s r, Spearman’s rho, Kendall’s tau were 0.67, 0.79, and 0.70, respectively with negligibly narrow 95% CIs. Across both arms of the pooled data, on average, predicted OS curves laid within the 95% CIs of the pooled OS KM-curves 92% of the time. Average deviation between the RMSTs under the model-predicted OS curves and pooled OS KM curves was 2%. In sensitivity analyses, the ranges for r, r, and t were (0.56-0.88), (0.69-0.89), and (0.61-0.80), respectively. Conclusions: Results indicate moderate-to-strong correlation between DFS and OS in early-stage treatment of EC/GEJC providing supportive evidence for the validation of DFS as a surrogate for OS. Our approach mitigates the lack of patient level data in endpoint correlation assessment but may be prone to changes in the predicted value of pre-recurrence death probability.
A phase 1a dose-escalation, multicenter trial of anti-claudin 18.2 antibody drug conjugate CMG901 in patients with resistant/refractory solid tumors.
Authors: Rui-hua Xu, Xiaoli Wei, Dongsheng Zhang, Miaozhen Qiu, Yang Zhang, Hongyun Zhao, Bo Chen, Joy Yan
Journal: Journal of Clinical Oncology (2023)

352 Background: CMG901, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate, has demonstrated potent preclinical anti-cancer activity through monomethyl auristatin E (MMAE)-mediated cytotoxicity with bystander killing, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Methods: This Phase 1a trial uses a modified 3+3 dose-escalation design to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity in subjects (ages 18-75 years) with advanced gastric, gastroesophageal junction (GEJ), pancreatic cancers, and other solid tumors. Eligible subjects are refractory and/or intolerant to standard therapies. CLDN18.2 expression was not required for study entry, but was retrospectively tested by the central lab. CMG901 was administered intravenously on Day 1 in 3-week (Q3W) cycle at doses of 0.3, 0.6, 1.2, 1.8, 2.2, 2.6, 3.0, and 3.4 mg/kg. Primary endpoints include safety and tolerability. Major efficacy endpoints include objective response rate (ORR) and disease control rate (DCR) based on RECIST v1.1. Pharmacokinetics (PK) and immunogenicity are also assessed. Results: As of August 4, 2022, 27 subjects (13 gastric/GEJ cancer and 14 pancreatic cancer patients) received CMG901 at dose levels up to 3.4 mg/kg. The median prior lines of systemic therapy were 2 (range: 1 to 5). Drug-related grade ≥3 adverse events (AEs) occurred in 3/27 (11.1%) patients. No drug-related grade 4 or 5 AEs were reported. MTD was not reached. In CLDN18.2-positive gastric/GEJ cancer patients, ORR and DCR were 75.0% and 100%, respectively, with ORR of 100% in the 2.6, 3.0, and 3.4 mg/kg Q3W dose cohorts. Median progression-free survival (mPFS) and median overall survival (mOS) were not reached yet. PK data showed that patients had low systemic exposure to unconjugated MMAE. Subsequent results will be presented. Conclusions: CMG901 was well-tolerated with preliminary promising clinical efficacy in patients with CLDN18.2-positive gastric/GEJ cancer. The Phase 1b dose-expansion trial in gastric/GEJ adenocarcinoma, pancreatic cancer, and other solid tumors is rapidly enrolling, with multiple pivotal (Phases 2 and 3) trials planned. Clinical trial information: NCT04805307 . [Table: see text]
Radiation exposure from diagnostic CT for young patients with colon cancer in the first 5 years after diagnosis.
Authors: Melissa Amy Lumish, Gary Tan, Usman Mahmood, Lawrence Dauer, Andrea Cercek, David Bates
Journal: Journal of Clinical Oncology (2023)

90 Background: Given the rise in colorectal cancer (CRC) in younger patients, this study aims to analyze the radiation exposure received by early onset colorectal cancer patients from diagnostic imaging performed in the first 5-years from diagnosis. Methods: A retrospective review of all patients (age ≤ 50 y) with stage I-III CRC who received at least 5 surveillance or staging body computed tomography (CT) scans in the 5 years from diagnosis was performed beginning in October 2015. The volume CT dose index (CTDIvol) and dose length product (DLP) were extracted; a previously validated Monte Carlo (MC) based software, VirtualDose (Virtual Phantoms, Inc., Albany, NY), was used to estimate organ dose to 19 organs based on the imaging mode parameters. The effective doses were calculated based on methods set forth in the International Commission on Radiological Protection ICRP No. 103 Publication. Results: A total of 107 patients were included (age range 25-50 years, median 44 years). The average effective dose per CT scan was 15.0 mSv range: 11.6 to 22.6 mSv) for male (n = 62) and 13.4 mSv (8.04 to 17.5 mSv) for female (n = 45) patients. The cumulative effective dose was greater than 100 mSv for 9 (8.4%) of patients and between 50 to &lt; 100 mSv for 28 (26.2%) of the patients in this study. Of the 107 patients, 23% (n = 25) of the patients recurred during the first 5 years. Conclusions: The majority of early-onset colorectal cancer patients in this study received a cumulative dose under 100 mSv, which is considered low risk according to a policy statement by the International Organization for Medical Physics. Since the majority of patients in this study received what is considered a low cumulative radiation dose from repeated CT imaging during the 5-year period after diagnosis, this may provide reassurance that repeated CT imaging, particularly for surveillance, is warranted. Individual risk will vary but the clinical benefits of clinical imaging outweigh the small, if any, risk of radiation-induced cancers in this patient cohort. [Table: see text]
Ramucirumab beyond progression plus TAS 102 in patients with advanced or metastatic adenocarcinoma of the stomach or the gastroesophageal junction, after treatment failure on a ramucirumab-based therapy: Final results of the phase II RE-ExPEL study.
Authors: Thorsten Oliver Goetze, Alexander Stein, Sylvie Lorenzen, Timorshah Habibzada, Eray Goekkurt, Peter Herhaus, Disorn Sookthai, Kristina Ihrig, Claudia Pauligk, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2023)

359 Background: Based on results of prior trials (TAGS, REGARD, RAINBOW), it seems promising to combine Ramucirumab (Ram) beyond progression (PD) with TAS-102 (trifluridine/tipiracil). The purpose of RE-ExPEL is to investigate the tolerability, safety and benefit of Ram beyond PD in combination with TAS-102 in advanced esophagogastric adenocarcinoma (EGA). Methods: This is a multicenter, non-randomized, open-label investigator initiated pilot trial. 20 ram-pretreated patients (pts) with advanced EGA were enrolled to a maximum of 4 cycles of ramucirumab 8mg/kg every two weeks (days 1, 15; qd28) plus TAS-102 35 mg/m 2 /p.o. bid (d1-5 and d8-12; qd28). Primary endpoint (EP) was tolerability and toxicity, defining a positive trial if SAE rate according (acc.) to CTCAE 5.0 will increase less than 30% (up to 55%) compared with results from TAGS (SAE-rate 43%). Secondary EPs are further safety data and efficacy data, OS, PFS and ORR. Results: 20 pts (20% female) were enrolled between Oct 2020 and Aug 2021, 20% gastric and 80% GEJ- cancers, 55% of pts with ECOG 0. Results of the final analysis showed that only 25% of pts had at least one SAE and the total no. of SAEs was 9, one with fatal outcome, all without relationship to systemic therapy and no SUSAR reported. RE-ExPEL was able to show a median OS of 9.07 mo (95% CI 5.42-10.09) and a DCR of 45%. 90% of pts got study medication in 3 rd line whereas 10% were even further line pts. Conclusions: The safety data showed a favorable safety profile with a low rate of severe toxicity for ram+TAS-102, maybe due to the long disease stabilization and therefore less tumor associated symptoms. Regarding the primary safety endpoint, the trial was positive with even a numerically lower SAE rate compared with TAGS. Furthermore, RE-ExPEL was able to show very promising efficacy data for the combination ram plus TAS-102 with median OS of 9.07 mo. Ram+TAS-102 seems to be more effective than TAS-102 alone acc. to TAGS-trial respecting the limitation of the RE-ExPEL one arm study design with only 20pts. The combination needs further evaluation in a randomized phase III trial. Clinical trial information: NCT04517747 .
ALTER-H006: A phase II study of TQB2450 plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after surgical resection.
Authors: Xianhai Mao, Xiaohui Duan, Dongde Wu, Cuncai Zhou, Yifeng Tian, Jinfang Zheng, Changbo Fu, Guohui Xu, Yannan Bai, Changxiong Wu
Journal: Journal of Clinical Oncology (2023)

TPS632 Background: Recurrence rate at 5 years for patients with early-stage HCC undergoing resection is between 50% and 70%. The optimal adjuvant treatment strategy for patients with resected HCC has not been proved and there is limited evidence to support a standard regimen for adjuvant treatment. Anlotinib, an oral small molecule antiangiogenic inhibitor, has shown promising anti-tumor activity and manageable toxicity as first or second-line treatment for patients with advanced HCC in an open-label phase II trial (NCT02809534). Anlotinib plus TQB2450, an anti-PD-L1 mAb, has shown anti-tumor activity in some solid tumors, such as biliary tract cancer (NCT03996408) and non-small cell lung cancer (NCT03910127). Here we investigate the efficacy and safety of this regimen as an adjuvant treatment for HCC with a high risk of recurrence after surgical resection. Methods: This is a single-arm, multicenter phase II trial. A total number of 37 patients with histologically or cytologically confirmed HCC will be enrolled. Eligible patients are aged 18-75, ECOG 0-1, Child-Pugh class A, 4~8 weeks after R0 resection with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b)portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. Patients enrolled receive anlotinib (12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year), whichever occurs first. Tumor assessment is performed at the end of the second cycle and every four cycles since that, according to RECIST v1.1. The primary endpoint is 1-year recurrence-free survival (RFS) rate. Secondary endpoints include RFS, 1-year overall survival (OS) rate, and safety. Recruitment for this study began in January 2022. Clinical trial information: NCT05111366 .
Effect of AXL on cholangiocarcinoma survival and sensitivity to cytotoxic chemotherapy.
Authors: Shohei Takaichi, Jennifer L Tomlinson, Mincheng Yu, Amro M Abdelrahman, Nathan W Werneburg, Gregory J Gores, Rory L Smoot
Journal: Journal of Clinical Oncology (2023)

591 Background: Cholangiocarcinoma (CCA) is a lethal disease with limited therapeutic options. We have demonstrated the interaction of Src-family kinase LCK with AXL, a TAM receptor tyrosine kinase (RTK), by phosphoproteomic analysis in CCA ( J Hepatol 2022). AXL is reported to act as a mechanism of acquired drug resistance in solid cancers. However, the role of AXL in CCA remains to be elucidated. Here, we investigated the significance of AXL expression as a potential therapeutic target in CCA. Methods: We first evaluated the expression levels of AXL in CCA and the associations with patient outcome using publicly available data from The Cancer Genome Atlas (TCGA). Next, to evaluate whether AXL inactivation sensitizes CCA cells to gemcitabine and cisplatin (GemCis) therapy as a standard therapy. AXL downregulation was achieved via siRNA approach and the selective inhibitor bemcentinib. We examined 50% inhibitory concentration (IC 50 ) value of HuCCT1, a well characterized CCA cell line, on GemCis therapy with and without AXL knockdown using CellTiter-Glo cell viability assay. Then we assessed the efficacy of the combinatorial therapy of GemCis and bemcentinib utilizing Calcusyn software. Finally, apoptosis was evaluated by Annexin V assay. In vivo efficacy was assessed using a SB-1 (murine CCA cell line) and syngeneic murine model of CCA in C57Bl/6J mice treated with vehicle, GemCis, bemcentinib, and the combination of GemCis and bemcentinib. Results: In the TCGA cohorts, AXL is significantly expressed in CCA (P &lt; 0.01), and disease-free survival and overall survival in low AXL expression group are significantly longer than those in high AXL expression group (P = 0.04, 0.01). In in vitro study, IC 50 value of GemCis was decreased from 685nM to 129nM after AXL knockdown. Synergy effect was observed with the value of CI = 0.17 and Fa = 0.50 in the combinatorial therapy. The combinatorial therapy caused significantly increased apoptosis compared to GemCis or bemcentinib alone (P &lt; 0.01, P &lt; 0.01). In in vivo study, the combinatorial therapy significantly suppressed the tumor growth compared to GemCis or bemcentinib alone (P = 0.04, 0.01). Conclusions: Targeting AXL sensitizes CCA cell lines and preclinical models to standard of care GemCis combinatorial therapy. Our study suggests that the addition of AXL targeted therapy to cytotoxic chemotherapy can increase the response in CCA patients and is a promising combination.
Colorectal endoscopic submucosal dissection using a concealable robotic add-on device: A comparative in vivo feasibility study.
Authors: Sang Hyun Kim, Bora Keum, Hyuk Soon Choi, Yoon Tae Jeen, Hoon Jai Chun, Daehie Hong
Journal: Journal of Clinical Oncology (2023)

128 Background: Appropriate tissue tension and clear visibility of the dissection area using traction are essential for effective and safe colonic endoscopic submucosal dissection (ESD). In this preclinical ex vivo and in vivo animal study, we developed a concealable robotic-assisted traction device and evaluated its performance in colorectal ESD. Methods: An experienced endoscopist performed ESD on an ex vivo porcine colon 18 times using our robot and 18 times using the conventional method. The outcome measures were procedure time, dissection speed, procedure-related adverse events, and blind dissection rate. We also conducted an in vivo feasibility study in live pigs. Robotic ESD was performed by experienced and novice endoscopist groups (n = 2, each). The outcomes included time to complete each ESD step, total procedure time, size of the dissected mucosa, rate of en bloc resection, and major adverse events. Results: Thirty-six colonic lesions were resected from ex vivo porcine colon samples. The total procedure time was significantly shorter in robotic ESD (RESD) than in conventional ESD (CESD) (20.1±4.1 vs. 34.3±8.3; P &lt; 0.05). The submucosal dissection speed was significantly higher in the RESD group than in the CESD group (36.8±9.2 vs. 18.1±4.7; P &lt; 0.05). The blind dissection rate was also significantly lower in the robotic group (12.8±3.4% vs. 35.1±3.9%; P &lt; 0.05). In an in vivo feasibility study, the robot was attached to the colonoscope and successfully inserted into the proximal colon without damaging the colonic wall, and ESD was successfully performed. There was no significant difference in the submucosal dissection speed between the groups (P = 0.465). Conclusions: When the concealable robot assisted the colonic ESD procedure, the dissection speed and safety profile improved significantly. Thus, our robotic device can provide a simple, effective, and safe multidirectional traction during colonic ESD. When the robot was assisting in the ESD procedure, the dissection speed improved significantly, especially in the novice endoscopists.
Identifying predictors of on-table adaptation for pancreas stereotactic body radiotherapy (SBRT).
Authors: Trudy Wu, Stephanie Yoon, Minsong Cao, Ann C. Raldow, Michael Xiang
Journal: Journal of Clinical Oncology (2023)

702 Background: There is growing interest in the use of stereotactic body radiotherapy (SBRT) to treat pancreatic cancer. The purpose of this study was to identify any clinical or dosimetric parameters that predict which individuals may benefit from on-table adaptation during pancreas SBRT with MRI-guided radiotherapy. Methods: This was a single center retrospective study of patients undergoing MRI-guided SBRT to the pancreas from 2016 to 2022. An online daily adaptive workflow was in place for all fractions according to pre-specified criteria. Pre-treatment clinical variables and dosimetric parameters on the patient’s simulation scan were recorded for each SBRT course, and their ability to predict for on-table adaptation was analyzed using ordinal logistic regression. The outcome measure was number of fractions adapted. Results: Seventy-three SBRT courses consisting of 365 fractions were included in this study. Median prescription dose was 40 Gy in five fractions (range, 33-50 Gy); 56% and 44% of courses were prescribed ≤ 40 Gy and &gt; 40 Gy, respectively. Median gross and planning target volume (GTV and PTV) coverage were 94.7% and 84.3%, respectively. Median number of fractions adapted per course was three, with overall 58% (211 out of 365) total fractions adapted. On univariable analysis, the prescription dose ( &gt; 40 Gy vs ≤ 40 Gy), GTV size, stomach V20 and V25, duodenum V20 and Dmax, large bowel V33 and V35, heterogeneity index, and gradient index were significant determinants of the use of on-table adaptation (all p &lt; 0.05). On multivariable analysis, only prescription dose remained significant (adjusted odds ratio 7.66, p = 0.003). Conclusions: Prescription dose in MRI-guided pancreas SBRT is the only reliable predictor of on-table adaptation. Providers should strongly consider utilization of adaptive technology when delivering ablative doses to the pancreas.[Table: see text]